Experimental Dermatology - 2023 - Kodali - Current Management of Generalized Pustular Psoriasis

Received: 28 November 2022 | Revised: 6 January 2023 | Accepted: 8 February 2023
DOI: 10.1111/exd.14765
REVIEW ARTICLE
Current management of generalized pustular psoriasis
Nilesh Kodali1 | Isabella Blanchard1 | Sruthi Kunamneni1 | Mark G. Lebwohl2
1
Department of Education, Rutgers New
Jersey Medical School, Newark, New Abstract
Jersey, USA
Generalized pustular psoriasis (GPP) is a rare subset of psoriasis involving episodes
2
Dermatology, The Icahn School of
Medicine at Mount Sinai, New York City,
of sterile pustules accompanied by inflammation and, often, systemic involvement.
New York, USA The inflammatory nature of GPP has potential for severe multisystem complications
Correspondence
including high-output cardiac failure, infections, digestive system issues, and disfig-
Mark G. Lebwohl, MD, FAAD Professor uring or lethal acute flare episodes. The disease tends to have higher prevalence in
& Chairman, Dermatology, Mount Sinai
–The Icahn School of Medicine at Mount
females and Asians. The IL-1/IL-36 inflammatory pathway is a critical facet of GPP's
Sinai, 5 East 98th St 5th Fl, New York, NY pathology. Genetic mutations that are associated with GPP include modifications of
10029, USA.
Email: [email protected]
Interleukin 36 Receptor Antagonist (IL36RN), Caspase Recruitment Domain Family
Member 14 (CARD14), Adaptor Related Protein Complex 1 Subunit Sigma 3 (AP1S3),
Myeloperoxidase (MPO) and Serpin Peptidase Inhibitor Clade A Member 3 (SERPINA3)
genes. Treatment guidelines for GPP are not well-entrenched. Currently, only one
GPP-specific treatment, the interleukin-36 receptor antagonist (IL-36Ra) spesolimab,
has been approved for use in the United States. Additional anti-IL-36 pathway thera-
pies are currently being developed. Other treatment options include other biologic
therapies such as IL-17 inhibitors, IL-23 inhibitors and TNFα inhibitors. Non-biologic
therapeutic options include retinoids, cyclosporine and methotrexate. Treatment op-
tions differ throughout the world; most countries utilize retinoids, cyclosporine and
methotrexate as first-line non-biologic options. China and United Kingdom have no
GPP-specific biologic therapies approved for use, while several biologic therapies are
approved for use in Japan. This review aims to serve as an update on the current
global management of GPP while also including relevant aspects of disease patho-
genesis, diagnosis, clinical presentation, histopathology, aetiology and epidemiology.
KEYWORDS
GPP, IL-36, IL-36Ra, IL-36RN, psoriasis, Spesolimab, systemic inflammation, treatment, von
Zumbusch
1 | I NTRO D U C TI O N subtype of psoriasis, is associated with innate immune system over-

activity that leads to the characteristic erythematous, scaly skin in-
Psoriasis is a common chronic inflammatory skin condition with a cluding pustules which can become confluent, forming lakes of pus. 2
wide variety of clinical presentations. Psoriasis Vulgaris (PV), the PP can manifest in a variety of ways including localized pustules, as
most common type of psoriasis, largely involves dysregulation of in acropustulosis or palmoplantar pustulosis (PPP), or as intermittent
the adaptive immune system.1 Pustular psoriasis (PP), a more rare (and often systemic) inflammatory illness, as in generalized pustular
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.
1204 |
wileyonlinelibrary.com/journal/exd Experimental Dermatology. 2023;32:1204–1218.
|
16000625, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/exd.14765 by Readcube (Labtiva Inc.), Wiley Online Library on [02/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
KODALI et al. 1205
psoriasis (GPP). PV makes up about 90% of all psoriasis cases,3 while include obesity, hypertension, hyperlipidaemia, diabetes mellitus
4,5
about 53%–65% of individuals with GPP have concurrent PV. and prior psoriasis.4,5
Generalized pustular psoriasis (GPP) is a rare and life-threatening The global mortality rate data for GPP are relatively limited and
psoriasis subtype characterized by recurring fever, systemic flush- confined to geographically localized studies. It is estimated to be
ing and sterile pustules.6 Clinical presentations include hundreds of between 2% and 7% worldwide, but this rate differs across coun-
grouped sterile pustules typically on an erythematous base. Pustules tries. Malaysian, Korean and Japanese studies found mortality rates
may coalesce into pus “lakes” during cutaneous flares, which are of 6.86%, 6.06% and 4.2%, respectively.5,16,17 A study in France re-
7
painful and can be disfiguring. GPP is a potentially life-threatening ported a serious complication rate of 17% and a mortality rate of
disease that may present with repeated acute flares involving sys- 2%.12
temic inflammation or as a chronic disease with intermittent flares. 8 The average hospital stay during a flare also differs in different
Although potentially life-threatening, management of GPP has been regions. A Malaysian study reported a mean stay of 10.3 days with
limited due to its rarity and lack of well-entrenched treatment guide- a range of 3 to 44 days.5 A study conducted in France from 2012 to
9
lines. Recent advancements in the pathogenesis of GPP have led to 2015 that included 569 inpatients reported a mean hospital stay was
novel treatment options such as spesolimab, a FDA-approved GPP- 11.5 days with 25% of patients being admitted to the ICU.18
10
specific treatment.
This review aims to provide an update on the management and
pathogenesis of GPP while also briefly investigating the relevant ep- 3 | A E TI O LO G Y
idemiology, aetiology and histopathology of the disease. Factors to
consider when ruling out differentials will also be explained to facil- A large spectrum of genetic mutations have been implicated in GPP.
itate timely and accurate diagnoses. Mutations in the IL36RN gene lead to a deficiency in the interleukin-
36 receptor antagonist (IL-36Ra) and have been thought to be a pri-
mary driver of GPP.19 Homozygous mutations of IL36RN were seen
2 | E PI D E M I O LO G Y to have more severe consequences than heterozygous mutations
and are inherited in an autosomal recessive manner. 20 Mutations in
Global GPP prevalence estimates have been a challenge to docu- the CARD14 gene are also implicated in GPP progression. These mu-
ment due to the heterogeneous prevalence of the disease across tations are inherited in an autosomal dominant manner and can up-
different locations and patient populations. Although there is no regulate the caspase recruitment domain family member 14 protein
definitive consensus on the global prevalence of GPP, a recent study (CARD14), which is specifically expressed in the skin and results in
utilized different geographical GPP prevalence results to estimate the activation of nuclear factor kappa B (NF-κB) signalling.19 Adaptor
a global prevalence range of 1.76 to 124 affected GPP patients per Related Protein Complex 1 Subunit Sigma 3 (AP1S3) mutations are
million people (0.0001% of the global population).11 also implicated in GPP and result in the destabilization of the adaptor
GPP prevalence varies across different countries. In France, a protein complex 1 (AP-1). 21 Autosomal recessive partial or complete
retrospective survey of 121 dermatological wards estimated a prev- loss-of-function mutations in the MPO gene that lead to a deficiency
12
alence of 1.76 affected GPP patients per million people. A differ- in the neutrophil enzyme myeloperoxidase (MPO) are also associ-
ent study done in Brazil looked at hospital databases from 2018 to ated with GPP.8
2020 and estimated the prevalence to be between 7 and 9 patients There are differences in the prevalence of the IL36RN mutation
per million.13 A third study used data from a Korean health insurance in GPP patients based on ethnic group and the presence of concur-
database between 2011 and 2015 and estimated a prevalence be- rent PV. One study analysed data from European, North African and
tween 88 and 124 patients per million people a year.11 Asian patients and found that 23.7% of this multi-ethnic patient cohort
Females tend to be more likely to present with GPP than males. carried IL36RN mutant alleles.19 A different study investigating Han
One study from France estimated that females were 1.3 times more Chinese GPP patients found that 60.47% of patients had an IL36RN
12
likely to have GPP than men. A similar study investigated in Brazil mutation, indicating a higher prevalence in this population.22 The aeti-
showed that 53% of GPP patients across public hospitals in Brazil ology of GPP without PV likely differs from that of GPP in conjunction
were female.13 Another study done in Malaysia assessed GPP pa- with PV. Approximately 53%–65% of patients with GPP have a prior
tients from 1989 to 2011 and found that GPP was twice as prevalent PV diagnosis.4,5 One study found that 82% of Japanese patients with
in females than males.5 In Thailand, GPP patients from 2005 to 2021 GPP alone had IL36RN mutations while only 10% of Japanese patients
were found to be 76.7% female.14 with both GPP and PV had the same mutation.23 CARD14, AP1S3 and
Prevalence also differs based on ethnicity and is estimated to MPO mutations have a lower association with GPP, with a prevalence
be higher in Asian populations compared to Caucasian populations. of at most 5.9%, 10.8% and 12.8%, respectively.8,24 Due to the genetic
Studies have estimated 7.46 GPP patients per million in Japan while basis of GPP, there is often a family history of psoriasis and GPP for
only 1.76 GPP patients per million in France.12,15 Although GPP can patients with GPP. In fact, a study conducted in Malaysia on 102 GPP
occur at any age, the mean age of onset is estimated to be in the patients found that 29% of the patients had a family history of psoriasis
fourth or early fifth decade of life.5,12 Common comorbidities of GPP and 11% of the patients had a family history of GPP.5
|
1206 KODALI et al.
Drug-related triggers are common, including steroid withdrawal, which affects the distal digits, are both types of localized pustular
antimalarials, beta-blockers, angiotensin-converting enzyme (ACE) psoriasis.31 GPP may occur in patients without a history of psoriasis
25,26
inhibitors and lithium. Pregnancy, menstruation, stress, upper and can present with or without plaque psoriasis.
respiratory tract infections and bacterial infections may also trig-
ger GPP.5 A recent study linked COVID-19 infection to subsequent
diagnosis or exacerbation of GPP, with an average time of 19 days 5 | D I AG N OS I S C R ITE R I A
between a COVID-19 infection and a pustule eruption. 27
Diagnostic criteria for GPP vary globally. The European Rare and
Severe Psoriasis Expert Network (ERASPEN) characterizes GPP as
4 | C LI N I C A L PR E S E NTATI O N primary, sterile and macroscopically visible epidermal pustules on
non-acral skin. The guidelines state that GPP can occur with or with-
Clinically, GPP is characterized by recurring, widespread and painful out systemic inflammation, with or without plaque psoriasis, and is
flares of sterile pustules 2–4 mm in diameter on inflamed and ery- either relapsing (>1 episode) or persistent (>3 months).32 Japanese
thematous skin. 28 These pustules are grouped together, can number criteria diagnose GPP based on 4 factors: (1) systemic symptoms
up to the hundreds and can become confluent to form “lakes of pus.” such as fever or fatigue; (2) systemic or extensive flush accompanied
When pustules dry up, they peel off and reveal either a red or normal by multiple sterile pustules; (3) neutrophilic subcorneal pustules his-
skin underneath. The severity and frequency of flares vary between tologically characterized by Kogoj's spongiform pustules, and (4) the
patients and between different flares in the same patient. Patients recurrence of these clinical and histologic findings. A definitive di-
may have multiple flares per year or one flare every few years and agnosis of GPP in Japan can be made in these patients who meet all
these episodes usually last from 2 to 5 weeks, but may continue for four criteria and GPP would be suspected in those who meet criteria
over 3 months. 20 2 and 3.6
GPP results in the protective functions of the skin being sig- Laboratory results that may be indicative of a GPP flare include
nificantly diminished or lost, which can manifest in several ways. elevated C-reactive protein (CRP) levels, elevated erythrocyte sedi-
Patients lose heat through the skin and generally lose temperature mentation rate (ESR), hypocalcemia, hypoalbuminemia, neutrophilia
control ability, becoming febrile or hypothermic. Because sepsis is and abnormal liver function tests. 20,29 During a GPP flare, high fever
the most common cause of death among patients with GPP, fever has been reported in about 24%–96% of patients with neutrophilia-
workup is important. Fluids are also lost through the skin, causing dominated leukocytosis being reported in about 30%–70% of pa-
hypotension and in some cases shock or acute renal failure. Other tients. 20 Iron deficiency anaemia is common. The type and severity
common symptoms include hypoalbuminemia resulting from pro- of both cutaneous and extracutaneous symptoms vary widely both
tein loss, anaemia resulting from iron loss, electrolyte imbalance and between and within patients, making GPP an unpredictable disease.
hypocalcemia resulting from electrolyte loss, arthritis and leukocy-
tosis. 20 Additionally, mucosal abnormalities can occur and lead to
cheilitis, genital lesions or geographic tongues. Serious complications 6 | H I S TO PATH O LO G Y
29
may lead to high-output cardiac failure and bilateral leg oedema.
There are several subtypes of GPP, including generalized and The histopathology of GPP involves the formation of spongiform pus-
localized types. The von Zumbusch type is generalized and is the tules of Kogoj in the subcorneal portion of the epidermis.6 These form
30
most severe form of GPP, leading to extreme symptoms. Another as a result of neutrophil accumulation beneath the stratum corneum
generalized form of GPP is annular pustular psoriasis (APP), which into necrotic epidermis in a sponge-like pattern.33,34 Acute GPP shows
is subacute and has mild systemic symptoms. It is characterized by pustules concentrated deeper in the epidermis than in chronic GPP.35
annular lesions with pustules, erythema, scaling and few laboratory Older GPP pustules may lack spongiform changes due to epidermal
abnormalities. However, there is debate as to whether or not APP is healing over time.36 Other GPP characteristics include a reduction in
a separate disease from GPP. 29 Another condition misclassified as a the granular layer causing abnormal maturation of keratinocytes and
form of GPP is acute generalized exanthematous pustulosis (AGEP), nuclei to be retained in cells at the stratum corneum.34,37 Psoriasiform
a generalized pustular eruption occurring within 24 h of ingestion of hyperplasia may also be present in those with GPP.38
20
a causative drug, most commonly antibiotics. It is characterized by
a sudden flare of sterile pustules and is usually short-lived, resolv-
ing within a few weeks. There is no relation to psoriasis and AGEP 7 | D I FFE R E NTI A L D I AG N OS I S
usually occurs in patients who do not have a history of psoriasis.
Juvenile pustular psoriasis and pustular psoriasis of pregnancy are 7.1 | Acute generalized exanthematous pustulosis
other generalized forms of GPP that affect the paediatric and preg-
nant populations, respectively.31 Localized forms are painful, but not GPP is often mistaken for acute generalized exanthematous pustu-
life-threatening. Palmoplantar pustular psoriasis, which affects the losis (AGEP), an acute onset pustular drug reaction. AGEP is gen-
palms and soles, and acrodermatitis continua of Hallopeau (ACH), erally less severe than acute GPP flares as the skin does not lose
|
KODALI et al. 1207
as much of its functionality.35 AGEP can be treated in 1 to 2 weeks (Figure 1). 6,51 This leads to a deficiency of interleukin-36 receptor
by withholding the causative medication. Abrupt onset, short du- antagonist (DITRA). These IL36RN gene variants are seen in about
ration, non-
recurrence, and no psoriasis or arthritis comorbidity 24% of patients with GPP52 and are associated with an earlier
are indicators of AGEP over GPP. Furthermore, if symptoms begin onset of disease.40 IL36RN mutations are not seen in individuals
shortly after using specific drugs and heal at the cessation of drug that have both PPP and GPP, indicating that IL36RN mutations may
35
use, an AGEP diagnosis is favoured. There are also histological dif- be responsible for a subtype of GPP without PPP. 53 The IL36RN
ferences between GPP and AGEP. GPP shows subcorneal pustules gene is primarily involved in regulating cutaneous innate immunity
of Kogoj with or without psoriasiform changes while AGEP shows by expressing the IL-36R antagonist (IL-36Ra), which suppresses
intraepidermal or subcorneal pustules with neutrophils, eosinophils, the IL-36 receptor (IL-36R) and its subsequent inflammatory cas-
31,35,39
necrotic keratinocytes and no psoriasiform changes. In AGEP, cade. Genetic alterations in the IL36RN gene produce dysfunc-
subcorneal pustules can be found touching intraepidermal pustules tional IL-36Ra that have decreased stability and faulty binding
and are spongiform, which is less prominent than in GPP.35 Although to IL-36R. Without an antagonizing modulation of IL-36R and a
AGEP typically has non-follicular pustules, the presence of follicular large induction of IL-36R agonists (such as IL-36α, IL-36β and IL-
35
pustules does not exclude AGEP. 36γ), 50,54–56 the IL-36R is unregulated and constantly activated. 53
This perpetuates a further downstream signalling cascade via NF-
κB and mitogen-a ctivated protein kinase (MAPK) that induces the
7.2 | Subcorneal pustular dermatosis expression of pro-inflammatory cytokines and chemokines such
as IL-1, IL-6 , IL-36, IL-8 , CXCL1 and CXCL20. 51,53 This massive cy-
Subcorneal pustular dermatosis (SPD) is another prominent differen- tokine storm activates various inflammatory mediators (such as
tial diagnosis for GPP. GPP and SPD present in a similar clinical and dendritic cells) and attracts a large neutrophil infiltrate to the epi-
histologic manner, and the histology of GPP and SPD can be indis- dermis. Activated dendritic cells secrete TNF and IL-23, which can
36
tinguishable. Both GPP and SPD are most common in adults over activate nearby Th17 cells. Th17 cells, upon activation, produce
40 years old and have similar recurring episodes of pustules.40,41 IL-17A, a pro-inflammatory cytokine that increases the synthesis
Inflammation resolves following treatment in several days in both of more IL-36R agonists such as IL-36α, IL-36β and IL-36γ. IL-17A
conditions as well.36 However, several clinical symptoms have also activates the NF-κ B pathway in fibroblasts, further increasing
been used to differentiate the diseases. SPD pustules arise as half- the cytokine storm. The large neutrophil infiltrate that proceeds
pustular, half-vesicular blisters whereas GPP pustules are commonly causes the typical pustular rash seen in GPP.46 Without regulation,
36
purely pinpoint. Histologic differences that are typically exclusive this IL-1/IL-36 inflammatory pathway is fixed in a constant positive
to GPP include psoriasiform changes, parakeratosis, elongated rete feedback loop that leads to worsening cutaneous and systemic ef-
ridges, spongiform pustules of Kogoj and acantholysis.36 fects. Other IL36RN gene mutations have also been identified in
individuals with GPP, proving IL36RN as a major therapeutic target
for GPP. 53
7.3 | Pustular drug eruption
Pustular drug eruption is another disease with a similar presenta- 8.2 | CARD14 variant
tion to GPP and is characterized by skin pustules and fever as a re-
sult of a negative drug interaction. However, unlike GPP, in pustular CARD14 gain-of-function variants have also been identified in GPP
drug eruption, there is no personal or family history of psoriasis. patients.33 CARD14 encodes a keratinocyte adaptor protein.33
Furthermore, there is a spontaneous resolution when the causative Normally, CARD14 is localized primarily in the basal and suprabasal
drug is stopped. Histological features unique to each disease are the epidermal layers; in diseased skin, expression of CARD14 is reduced
presence of eosinophils in the inflammatory infiltrate in pustular in the basal layer and upregulated in the suprabasal epidermal lay-
drug eruption and the presence of psoriasiform changes and spongi- ers.57 CARD14 activates NF-kB signalling, upregulating genes in ke-
42
form pustules of Kogoj in GPP. ratinocytes including chemokine ligand 20 (CCL20) and interleukin
Other differential diagnoses for GPP include folliculitis, miliaria, 8 (IL-8), initiating inflammatory recruitment and leading to epidermal
Candida infection and other localized forms of PP.43–45 inflammation.57 However, CARD14 variants were found only in a
small number of cases and were not as prevalent as IL36RN variants
in GPP patients.40
8 | PATH O G E N E S I S The CARD14 mutations provide further evidence that GPP with
PV has a distinct aetiology from GPP alone. In a direct sequencing
8.1 | IL-36RN mutation analysis of the coding region of CARD14 across different pheno-
types, it was found that none of the 11 GPP patients without PV had
The pathogenesis of GPP still remains under investigation, CARD14 mutations, while 4 of the 19 patients with GPP and PV had
but many familial GPP cases and some sporadic GPP cases are CARD14 variants. All four of these patients were heterozygous for
linked to a loss-of-f unction L27P substitution in the IL36RN gene the same CARD14 gene variant (c.526G>C).58
|
1208 KODALI et al.
F I G U R E 1 GPP pathogenesis. GPP pathogenesis primarily constitutes a large IL-36-dominated keratinocyte cytokine storm and epidermal
neutrophil aggregation.46–48 Epidermal neutrophil recruitment leads to pustular skin symptoms, and this recruitment is sustained and
long-lived due to an MPO deficiency.49 These keratinocyte cytokines stimulate various inflammatory mediators such as Th17 cells, dendritic
cells and neutrophils.46 Th17 stimulation causes a release of IL-17A, which increases IL-36 levels.46 Dendritic cells release TNF-α and IL-23,
which further stimulate Th17 and increase IL-36 levels.46 An MPO deficiency enhances the activity of neutrophil-derived proteases, which
continue to activate IL-36.49 An IL-36RN LOF mutation is the primary mutation implicated in GPP that produces dysfunctional IL-36Ra, which
normally functions to inhibit IL-36R, stop cytokine production and prevent inflammation.49 With no inhibitory protein for IL-36R, large
levels of IL-36 constitutively activate IL-36R, which further activates NF-κB and MAPK for more release of pro-inflammatory cytokines in a
constant positive loop.50 Various other mutations add to this increase in IL-36. An AP1S3 LOF mutation causes P62 buildup leading to NF-κB
activation and further IL-36 release.49 A CARD14 GOF mutation also οveractivates NF-κ Β for additional cytokine release. A rare SERPINA3
deletion (not shown in figure) can cause hyperactivation of IL-36 precursors and further increase IL-36 levels.49 Created with BioRender.com.
GPP, Generalized pustular psoriasis; IL, Interleukin; MPO, Myeloperoxidase; TNF, Tumor necrosis factor; IL-36Ra, Interleukin 36 receptor
antagonist; NF-κB, Nuclear factor kappa B; MAPK, Mitogen-activated protein kinases; LOF, Loss of function; GOF, Gain of function; AP1S3,
Adaptor related protein complex 1 subunit sigma 3; CARD14, Caspase recruitment domain family member 14; SERPINA3, Serpin peptidase
inhibitor clade A member 3.
|
KODALI et al. 1209
8.3 | AP1S3 mutation Serpin Peptidase Inhibitor Clade A Member 3 (SERPINA3) protein.
SERPINA3 inhibits the activity of cathepsin G, the primary serine
AP1S3 loss-of-function mutations are also implicated in GPP patho- protease involved in cleaving and activating IL-36 precursors. It is
genesis. These genetic abnormalities impair the AP-1 complex subu- postulated that with non-functional SERPINA3, there is a continu-
nit σ1C, which is involved in the assembly of clathrin-coated vesicles ous hyperactivation and build-up of functional IL-36, leading to the
for transport. 21 These mutations make the AP-1 complex less stable unregulated stimulation of the pro-inflammatory IL-36 pathway.65
and thus inhibit vesicle delivery between the trans-Golgi network Although implicated in GPP, SERPINA3 genetic deletions seem to be
and endosomes. 21,59 This disrupts endosomal translocation of Toll- relatively rare and present in only a few patient reports.66
Like-Receptor 3 (TLR-3) and can inhibit downstream signalling in
skin keratinocytes. 21 Cells with mutations in AP1S3 have decreased
autophagosome formation in keratinocytes, leading to p62 build- 9 | M A N AG E M E NT
up.60 Large quantities of p62 cause increased NFκB signalling, lead-
ing to the overexpression of IL-36α and subsequent overactivation Treatment guidelines for GPP are not well-established, and only
21,46
of the IL-36 pathway. one FDA-approved GPP-specific medication, spesolimab, is cur-
Like CARD14 variants, AP1S3 variants were found in fewer GPP rently approved for use in the United States. Recently, the European
cases than IL36RN. A study examining genetic differences in psori- Commission has approved spesolimab for use in adults with GPP
asis patients found that 4 out of the 251 GPP patients tested had flares in the European Union (EU) countries.67 Apart from the United
AP1S3 mutations. Out of those 4 GPP patients, 2 had both AP1S3 States and the EU countries, spesolimab and additional IL-36 path-
and IL36RN disease alleles.40 AP1S3 mutations across GPP, PPP way inhibitors are not currently approved for use globally. Biologic
and ACH may have different penetrance based on sex-specific fac- and non-biologic treatments not specific to GPP also exist (Figure 2).
tors, as almost all patients with AP1S3 disease alleles were female It should be noted that each of the treatment options discussed fol-
(p = 0.06).40 low conservative measures and could include inpatient admission
and supportive care in necessary circumstances. Due to varying co-
morbidities and levels of disease associated with GPP, treatments
8.4 | MPO deficiency should also be personalized.
Deficiency in the MPO gene encoding myeloperoxidase has only

recently been associated with GPP.49 Myeloperoxidase is a haem- 9.1 | Anti-IL-36 pathway therapy
containing peroxidase released by neutrophil granulocytes that ca-
talyses the formation of reactive oxygen species (ROS) including the Antagonistic anti-IL-36 receptor antibodies can be used to inhibit
peroxidation of chloride ions to form hypochlorous acid (HClO).49,61 the signalling pathway that causes active GPP flares and can be ef-
The antimicrobial activity of the MPO/HClO system is an integral fective even in cases with no deleterious IL36RN mutations.63 The
62
component of the innate immune response. MPO deficiency cor- anti-IL-36 receptor antibody spesolimab was recently approved to
related with the activity of IL-36-activating neutrophil proteases, treat acute GPP in the United States and functions by inhibiting the
stimulating the inflammatory IL-36 pathway.8 Phagocytosis assays IL-36R, which prevents the IL-36 inflammatory cascade (Figure 3).
of human and mouse cells with MPO deficiencies have revealed al- One randomized controlled trial demonstrated that a 900 mg intra-
tered neutrophil function and impaired efferocytosis, leading to a venous dose of spesolimab increased lesional clearance in a patient
8,63
prolonged neutrophil presence in inflammatory skin. Further cohort with active GPP flares after 1 week. Progress was measured
phenotypic analysis showed that individuals with MPO mutations via the Generalized Pustular Psoriasis Physician Global Assessment
more frequently had GPP with palmoplantar pustular psoriasis (GPPGA), which relies on professional evaluation of subjects' skin
(PPPP), tongue involvement, and family history of inflammatory skin condition in three categories: erythema, pustules and scaling/crust-
8
or joint diseases. Additionally, a younger age of onset was directly ing.80 Scores for each category range from 0 to 4, with 0 indicat-
8
correlated with a higher number of mutant MPO alleles. ing no visible symptoms and 4 indicating severe symptoms.81 After
one week, 43% of patients receiving spesolimab compared to 11%
of control patients achieved a GPPGA total score of 0 or 1, respec-
8.5 | SERPINA3 deletion tively. Additionally, 54% of patients receiving spesolimab compared
to 18% of the placebo cohort had a GPPGA pustulation subscore of
A rare, heterozygous loss-of-function deletion in the SERPINA3 gene zero, indicating no visible pustules, by the end of 1 week.82 It was
has been implicated in the progression of GPP. Sanger sequencing also found that groups receiving spesolimab had a higher incidence
determined that the same heterozygous SERPINA3 deletion was of infection.82 However, these infections were neither opportunistic
found in two different GPP patients. Correlation tests found that the nor severe.
rare genetic deletion was significantly associated with GPP preva- For rapid treatment of acute severe flares of GPP, a single intra-
lence.64 Normal expression of the SERPINA3 gene produces the venous dose of spesolimab may be effective. Spesolimab is currently
|
1210 KODALI et al.
F I G U R E 2 Current GPP treatment therapies. GPP can be managed through a variety of medications that all function differently (rcsb.
org).47,48,68–73 The only GPP-specific treatment that is currently FDA-approved in the United States is spesolimab, an anti-IL-36R antibody.74
Other treatments include additional inhibitors of the IL-36 pathway, IL-17 inhibitors, IL-23 inhibitors, TNF-α inhibitors, retinoids, calcineurin
inhibitors, anti-folate therapy and PDE4 inhibitors.47 Adapted from “Risk Factors of Dementia”, by BioRender.com (2022). Retrieved from
https://app.biorender.com/biorender-templates. GPP, Generalized pustular psoriasis; IL, Interleukin; TNF, Tumor necrosis factor; PDE,
Phosphodiesterase.
undergoing a 48-week safety and efficacy trial for the long-term Many other potential anti-IL-36 pathway therapies for GPP
management of GPP.10 Long-term management options being as- are still in development and testing. Imsidolimab is an IL-36 inhib-
sessed include a 600 mg subcutaneous spesolimab injection with itor currently undergoing a phase 3 clinical trial to investigate the
a 300 mg maintenance dose administered every 4 weeks, a 600 mg safety and efficacy of the drug over a 4-week and 24-week pe-
loading dose with a 300 mg maintenance dose administered every riod. One study examined imsidolimab's performance in 8 individ-
12 weeks and a 300 mg loading dose with a 150 mg maintenance uals with GPP over a 1-year period; patients received 750 mg of
dose administered every 12 weeks.10 IV imsidolimab on Day 1 and 100 mg of subcutaneous imsidolimab
|
KODALI et al. 1211
F I G U R E 3 GPP-specific Spesolimab treatment pathway. Epidermal IL-36 pathway in healthy, GPP, and spesolimab treatment.48,75,76
IL-36 is mainly expressed in epidermal, bronchial, intestinal epithelial and various immune cells.46 The IL-36 pathway regulates the balance
of pro-inflammatory and anti-inflammatory cytokine production at these tissue sites.46 (A) IL-36Ra is an IL-36R antagonist and immune
regulator.50 The Asp148 residue in the β11/12 loop of IL-36Ra prevents heterodimerization of IL-36R and the accessory protein IL-1RAcP and
attachment of IL-36 agonists through steric hindrance, blocking an inflammatory response through the pathway.77 (B) Many GPP patients
have dysfunctional IL-36Ra with limited binding capability and reduced stability.78 This leaves IL-36R open to bind with agonists including
IL-36α, IL-36β and IL-36γ.46,78 This causes uncontrolled activation of the IL-36 pro-inflammatory pathway, which has been implicated in
the pathogenesis of GPP.46 (C) Spesolimab is an antagonistic anti-IL-36 receptor antibody treatment that seeks out and binds to IL-36R.79
This binding prevents IL-36R agonists from binding to IL-36R and activating the inflammatory IL-36 pathway, leading to skin and pustular
clearance.79 Adapted from “Blank Comparison Pathway (Linear)”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biore
nder-templates. GPP, Generalized pustular psoriasis; IL, Interleukin; IL-1RAcP, Interleukin-1 receptor accessory protein.
every 4 weeks until Day 85. 83 It was found that at Week 4, 75% of efficacy of IL-1RAcP treatments for use in GPP because IL-1RacP is
patients demonstrated a positive clinical response on the Clinical expressed in many different cell types and inhibition could lead to
Global Impression (CGI) scale; this percentage held constant at various toxicities.79
83
Week 16. 2 of the 8 individuals had infections over the study pe-
riod; one individual acquired COVID-19, and the other acquired a
nosocomial infection. 83 9.2 | TNF-α inhibitors
Small molecules that inhibit IL-36γ are currently being developed
and could be applicable in the treatment of GPP. The endothelin re- TNF-α is associated with increased production of IL-36R agonists,
ceptor A antagonist ambrisentan (A-552) was identified as a potent which stimulate the IL-36 pathway that induces more TNF-α produc-
inhibitor of IL-36γ in humans. A-552 functions by inducing multiple tion in a continuous inflammatory loop. TNF-α inhibitors indirectly
inhibitory chemical and conformational changes in IL-36γ, diminish- suppress the expression of IL-36γ, which leads to reduced activation
ing IL-36γ's receptor-binding capability.84 Phenotyping of individuals of the pro-inflammatory IL-36 pathway.87,88 Adalimumab, infliximab
who lack the IL-36R-encoding gene revealed that they are not se- and certolizumab pegol are TNF-α inhibitors approved for use in
verely immunocompromised, further proving that the IL-36 pathway Japan.47 It should be noted that because GPP can be deadly and until
85
is a favourable therapeutic target with minimal side effects. recently specific treatments that work quickly in most patients were
Interleukin-1 receptor accessory protein (IL-1RAcP) antibodies not available, endpoints in trials for GPP often used any improve-
are another potential future management option for GPP patients. ment at all as a clinical endpoint.
When IL-36R binds with an agonist, it dimerizes with IL-1RAcP and In Japan, a case study examining a woman with GPP and psoriatic
activates the downstream Myd88 pathway.86 The Myd88 pathway arthritis (PA) identified that after the administration of a single 3 mg/
then can activate various pro-inflammatory transcription factors kg infliximab injection, the patient's pustular lesions cleared within
79
such as NF-κB, AP-1 and STAT3. Inhibiting IL-1RAcP's ability to 48 h. After a second 3 mg/kg injection, the patient's joint mobility
dimerize with IL-36R could prevent the IL-36 pathway overactiva- was notably improved. The patient received a 3 mg/kg infliximab
tion and the following inflammation cascade. However, additional injection every 8 weeks for long-term management and over a 12-
studies need to be conducted to determine the long-term safety and month period, no relapse of GPP or PA symptoms was noted.89
|
1212 KODALI et al.
While effective, TNF-α inhibitors do display adverse effects. In 225 Japanese subjects achieving a sPGA score of 0 or 1; serious in-
a Turkish study examining 156 GPP patients, TNF-α inhibitors were fections were not linked to risankizumab treatment.99
90
the only biologic GPP treatment that triggered paradoxical GPP.
An estimated 0.6%–5.3% of patients treated with TNF-α inhibitors
develop paradoxical GPP, and the most common drug associated 9.5 | Steroids
91,92
with paradoxical GPP was infliximab.
Other medications that have been used to manage GPP include sys-
temic steroids. Although systemic corticosteroids can quickly alle-
9.3 | IL-17 inhibitors viate pustular symptoms, significant side effects limit their clinical
effectiveness. Ryan and Baker determined that the management of
IL-17A and IL-17RA inhibitors include the medications secukinumab, GPP with systemic corticosteroids was associated with increased
ixekizumab and brodalumab. All three of these biologics are ap- deaths and decreased lasting remission.101 A retroactive study from
proved for use with GPP patients in Japan, and brodalumab is also Japan showed that hospitalized patients treated with only systemic
47,93
approved for use in Thailand and Taiwan. corticosteroids had an above-average mortality rate.17 Additionally,
A clinical trial investigating the efficacy of brodalumab found withdrawal of systemic corticosteroids following treatment fre-
that out of 12 GPP patients treated with brodalumab, 10 (83.3%) quently brought about increasingly severe GPP flares101 that are
patients had significant remission of GPP symptoms after 12 weeks. resistant to increasingly high steroid doses.
After one year, 11 of 12 patients (91.6%) achieved improvement or The topical steroid betamethasone dipropionate can also initiate
remission of GPP symptoms.93 GPP flares. Using steroid cream over large skin areas for an extended
There is no meaningful causative relationship between the use of amount of time for the management of PV or maintenance of GPP
brodalumab and suicidal ideation.94 In fact, there has only been one is not recommended due to the risk of inducing acute GPP if beta-
suicide documented worldwide after nearly half a decade of broda- methasone dipropionate is absorbed through compromised skin.102
95,96
lumab's use. As a preventative measure in the United States, Symptomatic treatment can also be employed to alleviate symp-
brodalumab prescriptions can only be administered going through toms associated with the disease. Triamcinolone acetonide ointment
the SILIQ risk evaluation and mitigation strategy program, a pro- and full-body wet wraps are used to reduce crusting and scaling and
94
gram designed to manage the risk of suicidal thoughts and actions. minimize discomfort, and whirlpool treatments clean the skin.103
Brodalumab should not be prescribed to individuals with a history of However, these treatments do not work quickly enough to suppress
suicidal thoughts.94 symptoms of an active outbreak.
Secukinumab and ixekizumab have also been established as ef-
fective treatments for GPP. Secukinumab was found to be effective
in a phase 3 trial involving 12 patients with GPP.97 After 3 to 4 weeks, 9.6 | Retinoids
72.7% of patients achieved a Psoriasis Area and Severity Index (PASI)
score of at least 75 and after 16 weeks, 83.3% of patients achieved a Retinoids were found to inhibit the differentiation of Th17 cells
98
PASI score of at least 75. Out of 5 individuals with GPP who were while also inducing T regulatory cell expression, promoting an anti-
assessed in a phase 3 trial for ixekizumab, 2 (40%) had completely inflammatory response.104 Retinoids may also limit the production
clear skin and 4 (80%) had achieved a PASI score of at least 75 after of TNFα, IL-1 and IL-6 .47,105 Acitretin can be effective in address-
97
12 weeks. All patients treated with ixekizumab had an improve- ing GPP, but when given as a maintenance dosage (10–3 0 mg/day),
97
ment in their PASI score. The most commonly reported adverse patients reported mild recurrence of symptoms at follow-up.106
47,93,97,98
event across all three IL-17 inhibitors was nasopharyngitis. Acitretin is teratogenic, which is also a concern when prescrib-
ing to individuals of child-b earing age, and its effects can last for
years after treatment.107 It is recommended that patients wait
9.4 | IL-23 inhibitors at least three years after ceasing acitretin treatment to become
pregnant due to the conversion of acitretin to etretinate when
IL-23 regulates the synthesis of IL-17, which in turn stimulates the syn- alcohol is consumed.108 In addition, capillary leak syndrome can
49
thesis of pro-inflammatory IL-36R agonists, further over-activating be a concern when prescribing acitretin; if this issue arises, reti-
the IL-36 pathway. IL-23 inhibitors guselkumab and risankizumab are noic acid treatment should cease immediately.109 Corticosteroid
6,47,99
approved for use in Japan. A Japanese phase 3 study evaluat- therapy may alleviate symptoms, and acitretin treatment should
ing the efficacy and safety of guselkumab found that out of 10 GPP be discontinued permanently in patients who exhibit capillary leak
patients treated with 50 mg guselkumab, 77.8% achieved treatment syndrome.110,111
success after 16 weeks of treatment. However, 28.6% of all patients As an alternative to acitretin, isotretinoin is also used in the
treated with guselkumab (n = 21) acquired nasopharyngitis over a management of GPP. Isotretinoin has a shorter teratogenic period
52-week period of treatment.100 A phase 3 trial for risankizumab than acitretin; it is recommended that patients wait at least one
demonstrated that a 150 mg subcutaneous dose resulted in 88% of month after ceasing isotretinoin treatment to become pregnant.112
|
KODALI et al. 1213
A notable concern when prescribing isotretinoin is immediate avail- applicable for patients with GPP who have been treated with acitre-
ability; all isotretinoin users must register in the iPLEDGE database tin and had minimal improvement or adverse side effects.
and individuals of child-bearing age must pledge to abstinence or
use two simultaneous methods of contraception, making it difficult
to maintain long-term treatment adherence.107,113 When successful, 9.9 | Apremilast
47
isotretinoin is faster-acting than other GPP medications.
Apremilast is a phosphodiesterase-4 (PDE4) inhibitor. PDE4 inhi-
bition has been shown to raise cyclic-AMP (cAMP) levels and de-
9.7 | Cyclosporine crease the secretion of IL-23,119,120 which may lead to decreased
epidermal inflammation. In a case report studying an individual
Cyclosporine is a calcineurin inhibitor that sequentially inhibits with PV, GPP and multiple comorbidities, apremilast was effective
nuclear factor of T cells (NFAT), a transcription factor responsible in achieving near-clearance of both PV and GPP after 2 to 3 weeks
for inflammatory cytokine production. This modulates immune re- of treatment.47,121 The patient began with a 10 mg dose, which was
sponses by decreasing the production of cytokines that activate increased by 10 mg each day until a maximum dose of 60 mg/day
pro-inflammatory T cells,114 preventing these T cells from further (30 mg twice/day) was established. The patient's PV and GPP were
activating the IL-36 pathway. Cyclosporine was found to be effec- completely cleared after 6 weeks of treatment; on the 60 mg/day
tive in addressing acute GPP episodes for some patients. In one ret- maintenance dose, the patient had no recurrence of PV or GPP for
roactive study, 102 GPP patients were treated with various potential at least 9 months.121
GPP treatments. Eight patients with acute GPP episodes responded Another study combined apremilast and infliximab to maintain
to cyclosporine; this included 2 patients with pustular psoriasis of GPP outbreak remission in a patient with GPP, ACH and multiple
pregnancy for whom cyclosporine treatment was successful in con- comorbidities including diabetes and neuropathy. The patient was
5
trolling an outbreak. The use of cyclosporine in the management of treated with apremilast and infliximab and had minimal GPP relapse
chronic GPP is less effective, with recurring flares being only par- for several months.122
tially controlled and the potential for hypertension to develop with Apremilast may be useful as a systemic therapy for individuals
extended use.5 who are unable to tolerate other medications due to side effects or
comorbidities. Furthermore, this medication is not contraindicated
in patients with infections and can be used in the management of
9.8 | Methotrexate acute and chronic GPP.121
Folic acid antagonists such as methotrexate may also be used to

treat GPP. Treatment of GPP with methotrexate was found to be less 9.10 | Global management and treatment options
effective in patients that had received prior steroid treatment.101
Many patients with GPP have associated renal disease, hepatic dis- Substantial variations in the management of GPP exist throughout
ease or a diabetes mellitus comorbidity; methotrexate should be the world. Biologic therapies have been approved for use in Japan,
used with caution in these patients.115 Furthermore, patients un- Taiwan, Thailand and the United States.9 In Brazil, Egypt, Germany,
dergoing treatment with methotrexate, especially patients over age China and Japan, patients are more likely to report directly to a
70, should be monitored for hematologic toxicity.116 Methotrexate dermatologist, possibly making timely and accurate diagnosis more
is a particularly common treatment option for paediatric patients likely.9 Furthermore, drug availability for treatment varies largely
with GPP; although hepatic function while on methotrexate is a worldwide. Countries such as the United States and Russia have bet-
pressing concern in adult cases, no cases of hepatic fibrosis have ter drug availability than other countries including the Philippines
been reported in children using methotrexate to manage psoriasis. and Indonesia.123,124 Better drug availability allows these countries
Methotrexate is teratogenic and should not be used to treat preg- to provide more immediate and personalized treatment options
nant individuals with GPP.117 while countries with less drug availability resort to alternative non-
Methotrexate is slower-acting than other GPP treatments. Due to specific therapies or supportive care available for use. In many coun-
its slow onset of action, attaining an adequate dose may take several tries, conventional PV medications and biologics are the first-line
weeks; it is recommended that the weekly dose begin between 5 mg treatments for GPP.125
and 15 mg and be increased by 2.5 mg each week as tolerated until Retinoids or cyclosporine are the first-line treatments for the
symptoms are manageable.105 Paediatric patients should receive no management of GPP in Japan.126 With the availability of speso-
more than 25 mg of methotrexate weekly.118 Methotrexate therapy limab, it is likely that prescribing patterns will take into account
may be more helpful for the management of chronic GPP than acute this reliably and rapidly effective treatment. Several biologic
GPP due to its slow onset of action. In circumstances where other agents have been approved for use in treating GPP in Japan when
medications are not tolerated, methotrexate may be valuable for the a refractory response to non-biologic therapies is observed.124 IL-
treatment of acute GPP. Treatment via methotrexate is particularly 17 inhibitors including secukinumab, ixekizumab and brodalumab
|
1214 KODALI et al.
are licensed for the treatment of PV and GPP in Japan.124 TNF-α The approval of spesolimab in the United States has brought
inhibitors and IL-23 inhibitors are also approved for the treat- about a need for updated guidelines for the treatment and manage-
ment of severe GPP that is unresponsive to traditional first-line ment of GPP.31,74 Experiments that provide more robust data com-
therapies.126 paring the side effects and efficacy of both biologic and non-biologic
In Europe, no biologic agents are approved for the treatment of medications for GPP are necessary to inform novel GPP treatment
GPP, so systemic non-biologic agents and biologics used for PV are guidelines.
typically used for treatment and management of GPP.124 PV biolog- Disparities in GPP treatment options exist for women of child-
ics are, however, less effective in treating GPP than in PV. Common bearing age due to the teratogenicity of several medications.47
non-biologic systemic agents used for the treatment and manage- Currently, individuals of child-bearing age who manage chronic GPP
ment of GPP in Europe include acitretin, cyclosporine A and meth- with retinoids or folic acid antagonists must either abstain from be-
otrexate. Corticosteroids and acitretin are the only systemic drugs coming pregnant or discontinue therapy prior to conceiving. Non-
that are licensed in Germany to treat GPP.115 As mentioned above, teratogenic therapies should be investigated and assessed for use
the availability of spesolimab will likely impact treatment of GPP in in pregnant individuals. Prompt development and approval of addi-
Europe. tional biologic therapies for the treatment and management of GPP
Biologic agents specific to GPP are also not approved in China. In may help to address this issue.
addition to systemic therapies, topical treatments are recommended
with the aim of maintaining skin hygiene and integrity. Topical cala-
mine is used to minimize pustules, decrease irritation and maintain 11 | CO N C LU S I O N S A N D PE R S PEC TI V E S
skin hygiene during outbreaks.125 Herbal topical and systemic ther-
apies are often used on their own or in combination with Western GPP is a severe inflammatory condition that can be life-threatening.105
125
treatments. During flares, skin is compromised such that patients are at signifi-
It is vital that additional medications that work quickly to alle- cant risk of hypothermia and infection, particularly in a hospital en-
viate the symptoms of active GPP outbreaks are developed, tested vironment. Additional potentially debilitating complications include
and approved for use. Methods to predict GPP outbreaks should the potential for systemic inflammation and high-
output cardiac
also be elucidated and would allow for more effective lifelong man- failure. 20 Acute GPP episodes can be disfiguring and lethal, and it is
agement of the condition. critical to address flares as quickly as possible to minimize the risk of
severe adverse events.47
The main inflammatory pathway that has been implicated in GPP
10 | M A J O R O PE N Q U E S TI O N S is the IL-36 pathway.19 Various mutations of several genes, includ-
ing IL36RN, CARD14, AP1S3, MPO and SERPINA3 alter the regulation
Numerous gaps of knowledge exist in the understanding of GPP. of this inflammatory pathway, leading to uncontrolled inflammation
One notable concern when managing patients with GPP is predict- and typical pustular symptoms.49,64
ing and recognizing acute flares as soon as possible. Rapid recogni- Ideal treatments for GPP would rapidly address and clear
tion of acute illness can minimize the duration and severity of patient cutaneous flares to minimize patient disfigurement and dis-
discomfort and reduce the risk of complications arising from disease tress, and minimize the severity of GPP-related complications. 31
31
pathology. Methods of detecting flares should involve repeated Maintenance therapies that can be used long-term (with min-
clinical and patient-reported assessment and documentation of the imal side effects) and are effective in preventing flares are also
patient's baseline skin condition, allowing for small changes to be needed. 31 Although treatments are limited, the anti-IL-36 recep-
recognized and addressed quickly. Longitudinal studies of individu- tor antibody spesolimab recently became the first FDA-approved
als with GPP could be carried out to monitor lifestyle factors, skin GPP-specific therapeutic agent in the United States for use in
condition and other symptoms; this will allow for more accurate pre- treating acute GPP flares.74 The long-term efficacy of spesolimab
diction and identification of flares. in preventing GPP flares has yet to be elucidated, though clinical
Furthermore, variations in response to spesolimab and non- trials assessing the medication's effectiveness over a 48-week pe-
biologic therapies across different ethnic groups should be mea- riod are currently underway.10 The availability of specific biologic
31
sured and quantified. Different ethnic groups have different allele therapy for the treatment of GPP may change GPP maintenance
frequencies of mutations across the range of different genes impli- guidelines in the United States.74 Depending on the presence and
19,22
cated in the pathogenesis of GPP. As such, the most effective severity of side effects noted in the long-term clinical trial of spe-
treatments available for GPP may vary between different ethnic solimab, this medication may be a suitable alternative for address-
groups with disparate GPP gene mutations. However, recruitment ing chronic GPP to retinoids and folic acid antagonists, which have
of a sufficient number of patients by ethnicity may be a challenge the drawbacks of teratogenicity and other side effects that can
due to the rarity of the condition.31,82 Retroactive studies could be hinder long-term treatment.47
employed to determine relationships between ethnicity and the ef- Additional biologic options for the treatment of acute GPP and
ficacy of a particular medication in order to increase cohort sizes. maintenance of chronic GPP should be investigated for use in the
|
KODALI et al. 1215
7. Kharawala S, Golembesky AK, Bohn RL, Esser D. The clinical, hu-

United States.31 Updated guidelines for the management of GPP manistic, and economic burden of generalized pustular psoriasis:
should be developed with biologic agents in mind.31 a structured review. Expert Rev Clin Immunol. 2020;16(3):239-252.
doi:10.1080/1744666X.2019.1708193
8. Haskamp S, Bruns H, Hahn M, et al. Myeloperoxidase modulates
AU T H O R C O N T R I B U T I O N S
inflammation in generalized pustular psoriasis and additional rare
N.K. and M.L. conceived of the paper. N.K., I.B. and S.K. wrote and
pustular skin diseases. Am J Hum Genet. 2020;107(3):527-538.
edited the initial draft of the paper. N.K and I.B. created the figures. doi:10.1016/j.ajhg.2020.07.001
N.K. and M.L. edited and completed the final draft of the paper. All 9. Strober B, Leman J, Mockenhaupt M, et al. Unmet educational needs
authors have approved the final paper. and clinical practice gaps in the management of generalized pustu-
lar psoriasis: global perspectives from the front line. Dermatol Ther
(Heidelb). 2022;12(2):381-393. doi:10.1007/s13555-021-0 0661-2
AC K N OW L E D G M E N T S 10. Morita A, Choon SE, Bachelez H, et al. Design of Effisayil™ 2: a
None. randomized, double-blind, placebo-controlled study of spesolimab
in preventing flares in patients with generalized pustular psori-
asis. Dermatol Ther (Heidelb). 2023;13(1):347-359. doi:10.1007/
F U N D I N G I N FO R M AT I O N
s13555-022-0 0835-6
None. 11. Prinz JC, Choon SE, Griffiths CEM, et al. Prevalence, comorbidities
and mortality of generalized pustular psoriasis: a literature review.
C O N FL I C T O F I N T E R E S T S TAT E M E N T J Eur Acad Dermatol Venereol. 2023;37(2):256-273. doi:10.1111/
jdv.18720
None.
12. Augey F, Renaudier P, Nicolas JF. Generalized pustular psoria-
sis (Zumbusch): a French epidemiological survey. Eur J Dermatol.
DATA AVA I L A B I L I T Y S TAT E M E N T 2006;16(6):669-673.
Data sharing is not applicable to this article as no new data were cre- 13. Duarte GV, Esteves de Carvalho AV, Romiti R, et al. Generalized
pustular psoriasis in Brazil: a public claims database study.
ated or analyzed in this study.
JAAD Int. 2022;6:61-67. Published 2022 Jan 12. doi:10.1016/j.
jdin.2021.12.001
F I N A N C I A L D I S C LO S U R E S 14. Chaiyabutr C, Silpa-archa N, Wongpraprarut C, Likittanasombat
None. S, Phumariyapong P, Chularojanamontri L. An analysis of psoriasis
hospitalisation in Thailand. Arch Dermatol Res. Published Online
October 29. 2022. doi:10.1007/s00403-022-02429-w
R E P R I N T R EQ U E S T S
15. Ohkawara A, Yasuda H, Kobayashi H, et al. Generalized pus-
None. tular psoriasis in Japan: two distinct groups formed by differ-
ences in symptoms and genetic background. Acta Derm Venereol.
ORCID 1996;76(1):68-71. doi:10.2340/00015555766871
16. Jin H, Cho HH, Kim WJ, et al. Clinical features and course of gener-
Nilesh Kodali https://orcid.org/0000-0003-2092-9469
alized pustular psoriasis in Korea. J Dermatol. 2015;42(7):674-678.
Isabella Blanchard https://orcid.org/0000-0002-4995-031X doi:10.1111/1346-8138.12863
Sruthi Kunamneni https://orcid.org/0000-0002-6443-6079 17. Miyachi H, Konishi T, Kumazawa R, et al. Treatments and out-
comes of generalized pustular psoriasis: a cohort of 1516 patients
in a nationwide inpatient database in Japan. J Am Acad Dermatol.
REFERENCES 2022;86(6):1266-1274. doi:10.1016/j.jaad.2021.06.008
1. Hu P, Wang M, Gao H, et al. The role of helper T cells in psori- 18. Vmx A. Medicom International Conference Series in Dermatology.
asis. Front Immunol. 2021;12:788940. Published 2021 Dec 15. 24.
doi:10.3389/fimmu.2021.788940 19. Sugiura K. The genetic background of generalized pustular
2. Bachelez H. Pustular psoriasis: the Dawn of a new era. Acta Derm psoriasis: IL36RN mutations and CARD14 gain-of-function
Venereol. 2020;100(3):adv00034. doi:10.2340/00015555-3388 variants. J Dermatol Sci. 2014;74(3):187-192. doi:10.1016/j.
3. Griffiths CE, Barker JN. Pathogenesis and clinical features jdermsci.2014.02.006
of psoriasis. Lancet. 2007;370(9583):263-271. doi:10.1016/ 20. Choon SE, Navarini AA, Pinter A. Clinical course and charac-
S0140-6736(07)61128-3 teristics of generalized pustular psoriasis. Am J Clin Dermatol.
4. Löfvendahl S, Norlin JM, Schmitt-Egenolf M. Comorbidities 2022;23(Suppl 1):21-29. doi:10.1007/s40257-021-0 0654-z
in patients with generalized pustular psoriasis-a nationwide 21. Setta-Kaffetzi N, Simpson MA, Navarini AA, et al. AP1S3 muta-
population-based register study. J Am Acad Dermatol. 2022;S0190- tions are associated with pustular psoriasis and impaired toll-
9622(22)02794-3. doi:10.1016/j.jaad.2022.09.049 like receptor 3 trafficking. Am J Hum Genet. 2014;94(5):790-797.
5. Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew SF. doi:10.1016/j.ajhg.2014.04.005
Clinical profile, morbidity, and outcome of adult- onset gener- 22. Li Z, Yang Q, Wang S. Genetic polymorphism of IL36RN in Han pa-
alized pustular psoriasis: analysis of 102 cases seen in a tertiary tients with generalized pustular psoriasis in Sichuan region of China:
hospital in Johor, Malaysia. Int J Dermatol. 2014;53(6):676-684. a case- control study. Medicine (Baltimore). 2018;97(31):e11741.
doi:10.1111/ijd.12070 doi:10.1097/MD.0000000000011741
6. Fujita H, Terui T, Hayama K, et al. Japanese guidelines for the man- 23. Sugiura K, Takemoto A, Yamaguchi M, et al. The majority of gen-
agement and treatment of generalized pustular psoriasis: the new eralized pustular psoriasis without psoriasis vulgaris is caused by
pathogenesis and treatment of GPP. J Dermatol. 2018;45(11):1235- deficiency of interleukin-36 receptor antagonist. J Invest Dermatol.
1270. doi:10.1111/1346-8138.14523 2013;133(11):2514-2521. doi:10.1038/jid.2013.230
|
1216 KODALI et al.
24. Takeichi T, Akiyama M. Generalized pustular psoriasis: clin- examined at Kurume University. Br J Dermatol. 2017;176(1):168-
ical management and update on autoinflammatory as- 175. doi:10.1111/bjd.14780
pects. Am J Clin Dermatol. 2020;21(2):227-236. doi:10.1007/ 42. Spencer JM, Silvers DN, Grossman ME. Pustular eruption after drug
s40257-019-0 0492-0 exposure: is it pustular psoriasis or a pustular drug eruption? Br J
25. Westphal DC, Schettini APM, de Souza PP, Castiel J, Chirano CA, Dermatol. 1994;130(4):514-519. doi:10.1111/j.1365-2133.1994.
Santos M. Generalized pustular psoriasis induced by systemic tb03389.x
steroid dose reduction. An Bras Dermatol. 2016;91(5):664-666. 43. Guerra KC, Toncar A, Krishnamurthy K. Miliaria. StatPearls.
doi:10.1590/abd1806-4841.20163804 StatPearls Publishing; 2022. Accessed November 24, 2022. http://
26. Balak DM, Hajdarbegovic E. Drug-induced psoriasis: clinical www.ncbi.nlm.nih.gov/books/NBK537176/
perspectives. Psoriasis (Auckl). 2017;7:87-94. doi:10.2147/PTT. 44. Uehara M. Palmar and plantar pustulosis elicited by Candida anti-
S126727 gen. Arch Dermatol. 1978;114(5):730-731.
27. Goyal PK, Mohammed TO, Mahmoud A, Zaidi AJ, Nguyen CV. 45. Lin HS, Lin PT, Tsai YS, Wang SH, Chi CC. Interventions for bac-
COVID-19 infection leading to acute pustular dermatoses. terial folliculitis and boils (furuncles and carbuncles). Cochrane
Arch Dermatol Res. Published Online November 1. 2022;1- 13. Database Syst Rev. 2021;2(2):CD013099. Published 2021 Feb 26.
doi:10.1007/s00403-022-02450-z doi:10.1002/14651858.CD013099.pub2
28. Baker H, Ryan TJ. Generalized pustular psoriasis. A clinical and ep- 46. Marrakchi S, Puig L. Pathophysiology of generalized pustular pso-
idemiological study of 104 cases. Br J Dermatol. 1968;80(12):771- riasis. Am J Clin Dermatol. 2022;23(Suppl 1):13-19. doi:10.1007/
793. doi:10.1111/j.1365-2133.1968.tb11947.x s40257-021-0 0655-y
29. Ly K, Beck KM, Smith MP, Thibodeaux Q, Bhutani T. Diagnosis and 47. Krueger J, Puig L, Thaçi D. Treatment options and goals for pa-
screening of patients with generalized pustular psoriasis. Psoriasis tients with generalized pustular psoriasis. Am J Clin Dermatol.
(Auckl). 2019;9:37-42. Published 2019 Jun 20. doi:10.2147/PTT. 2022;23(Suppl 1):51-6 4. doi:10.1007/s40257-021-0 0658-9
S181808 48. BioRender. Accessed November 24, 2022. https://biorender.com/
30. Wang Q, Liu W, Zhang L. Clinical features of von Zumbusch type 49. Zhou J, Luo Q, Cheng Y, Wen X, Liu J. An update on genetic
of generalized pustular psoriasis in children: a retrospective basis of generalized pustular psoriasis (review). Int J Mol Med.
study of 26 patients in southwestern China. An Bras Dermatol. 2021;47(6):118. doi:10.3892/ijmm.2021.4951
2017;92(3):319-322. doi:10.1590/abd1806-4841.20175536 50. Johnston A, Xing X, Wolterink L, et al. IL-1 and IL-36 are dominant
31. Gooderham MJ, Van Voorhees AS, Lebwohl MG. An update cytokines in generalized pustular psoriasis. J Allergy Clin Immunol.
on generalized pustular psoriasis. Expert Rev Clin Immunol. 2017;140(1):109-120. doi:10.1016/j.jaci.2016.08.056
2019;15(9):907-919. doi:10.1080/1744666X.2019.1648209 51. Marrakchi S, Guigue P, Renshaw BR, et al. Interleukin-36–receptor
32. Navarini AA, Burden AD, Capon F, et al. European consensus antagonist deficiency and generalized pustular psoriasis. N Engl J
statement on phenotypes of pustular psoriasis. J Eur Acad Dermatol Med. 2011;365(7):620-628. doi:10.1056/NEJMoa1013068
Venereol. 2017;31(11):1792-1799. doi:10.1111/jdv.14386 52. Uppala R, Tsoi LC, Harms PW, et al. “Autoinflammatory psoriasis”—
33. Fujita H, Gooderham M, Romiti R. Diagnosis of generalized pus- genetics and biology of pustular psoriasis. Cell Mol Immunol.
tular psoriasis. Am J Clin Dermatol. 2022;23(Suppl 1):31-38. 2021;18(2):307-317. doi:10.1038/s41423-020-0519-3
doi:10.1007/s40257-021-0 0652-1 53. Onoufriadis A, Simpson MA, Pink AE, et al. Mutations in IL36RN/
34. Hoegler KM, John AM, Handler MZ, Schwartz RA. Generalized IL1F5 are associated with the severe episodic inflammatory skin
pustular psoriasis: a review and update on treatment. J Eur Acad disease known as generalized pustular psoriasis. Am J Hum Genet.
Dermatol Venereol. 2018;32(10):1645-1651. doi:10.1111/jdv.14949 2011;89(3):432-437. doi:10.1016/j.ajhg.2011.07.022
35. Kardaun SH, Kuiper H, Fidler V, Jonkman MF. The histo- 54. Bozonnat A, Assan F, LeGoff J, Bourrat E, Bachelez H. SARS-CoV-2
pathological spectrum of acute generalized exanthem- infection inducing severe flare up of deficiency of interleukin
atous pustulosis (AGEP) and its differentiation from thirty-six (IL-36) receptor antagonist (DITRA) resulting from a mu-
generalized pustular psoriasis. J Cutan Pathol. 2010;37(12):1220- tation invalidating the activating cleavage site of the IL-36 recep-
1229. doi:10.1111/j.1600-0560.2010.01612.x tor antagonist. J Clin Immunol. 2021;41(7):1511-1514. doi:10.1007/
36. Khosravi-Hafshejani T, Dutz JP. Chronic annular pustular psoriasis s10875-021-01076-6
resembling subcorneal pustular dermatosis: a case report. SAGE 55. Sugiura K, Takeichi T, Kono M, et al. A novel IL36RN/IL1F5 ho-
Open Med Case Rep. 2019;7:2050313X19857392. Published 2019 mozygous nonsense mutation, p.Arg10X, in a Japanese patient
Jun 20. doi:10.1177/2050313X19857392 with adult- onset generalized pustular psoriasis. Br J Dermatol.
37. Bachelez H, Barker J, Burden AD, Navarini AA, Krueger JG. 2012;167(3):699-701. doi:10.1111/j.1365-2133.2012.10953.x
Generalized pustular psoriasis is a disease distinct from psoriasis 56. Mulero JJ, Pace AM, Nelken ST, et al. IL1HY1: a novel interleu-
vulgaris: evidence and expert opinion. Expert Rev Clin Immunol. kin-
1 receptor antagonist gene. Biochem Biophys Res Commun.
2022;18(10):1033-1047. doi:10.1080/1744666X.2022.2116003 1999;263(3):702-706. doi:10.1006/bbrc.1999.1440
38. Milora KA, Fu H, Dubaz O, Jensen LE. Unprocessed interleukin- 57. Jordan CT, Cao L, Roberson ED, et al. PSORS2 is due to mutations
36α regulates psoriasis- like skin inflammation in cooperation in CARD14. Am J Hum Genet. 2012;90(5):784-795. doi:10.1016/j.
with Interleukin-1. J Invest Dermatol. 2015;135(12):2992-3 000. ajhg.2012.03.012
doi:10.1038/jid.2015.289 58. Sugiura K, Muto M, Akiyama M. CARD14 c.526G>C (p.Asp176His)
39. Feldmeyer L, Heidemeyer K, Yawalkar N. Acute generalized ex- is a significant risk factor for generalized pustular psoriasis with
anthematous pustulosis: pathogenesis, genetic background, clini- psoriasis vulgaris in the Japanese cohort. J Invest Dermatol.
cal variants and therapy. Int J Mol Sci. 2016;17(8):1214. Published 2014;134(6):1755-1757. doi:10.1038/jid.2014.46
2016 Jul 27. doi:10.3390/ijms17081214 59. Hirst J, Barlow LD, Francisco GC, et al. The fifth adaptor pro-
40. Twelves S, Mostafa A, Dand N, et al. Clinical and genetic differ- tein complex [published correction appears in PLoS Biol. 2012
ences between pustular psoriasis subtypes. J Allergy Clin Immunol. Mar;10(3). 10.1371/annotation/89dff893-c156-4 4bb-a731-
2019;143(3):1021-1026. doi:10.1016/j.jaci.2018.06.038 bfcc91843583]. PLoS Biol. 2011;9(10):e1001170. doi:10.1371/
41. Hashimoto T, Teye K, Ishii N. Clinical and immunological stud- journal.pbio.1001170
ies of 49 cases of various types of intercellular IgA dermato- 60. Mahil SK, Twelves S, Farkas K, et al. AP1S3 mutations
sis and 13 cases of classical subcorneal pustular dermatosis cause skin autoinflammation by disrupting keratinocyte
|
KODALI et al. 1217
autophagy and up-regulating IL-36 production. J Invest Dermatol. 80. Burden AD, Choon SE, Gottlieb AB, Navarini AA, Warren RB.
2016;136(11):2251-2259. doi:10.1016/j.jid.2016.06.618 Clinical disease measures in generalized pustular psoriasis. Am J Clin
61. Zhou Y, Pei W, Wang C, et al. Reactive oxygen species: rhodamine- Dermatol. 2022;23(1):39-50. doi:10.1007/s40257-021-0 0653-0
modified Upconversion nanophosphors for Ratiometric de- 81. Choon SE, Lebwohl MG, Marrakchi S, et al. Study protocol of the
tection of Hypochlorous acid in aqueous solution and living global Effisayil 1 phase II, multicentre, randomised, double-blind,
cells (small 17/2014). Small. 2014;10(17):3592. doi:10.1002/ placebo-controlled trial of spesolimab in patients with general-
smll.201470106 ized pustular psoriasis presenting with an acute flare. BMJ Open.
62. Aratani Y. Myeloperoxidase: its role for host defense, inflamma- 2021;11(3):e043666. Published 2021 Mar 30. doi:10.1136/
tion, and neutrophil function. Arch Biochem Biophys. 2018;640:47- bmjopen-2020-0 43666
52. doi:10.1016/j.abb.2018.01.004 82. Bachelez H, Choon SE, Marrakchi S, et al. Trial of Spesolimab for
63. Bachelez H, Choon SE, Marrakchi S, et al. Inhibition of the interleu- generalized pustular psoriasis. N Engl J Med. 2021;385(26):2431-
kin-36 pathway for the treatment of generalized pustular psoriasis. 2440. doi:10.1056/NEJMoa2111563
N Engl J Med. 2019;380(10):981-983. doi:10.1056/NEJMc1811317 83. A study to evaluate the efficacy and safety of imsidolimab
64. Frey S, Sticht H, Wilsmann-Theis D, et al. Rare loss-of-function (ANB019) in adults with generalized pustular psoriasis - Study
mutation in SERPINA3 in generalized pustular psoriasis. J Invest Results -ClinicalTrials.gov. Accessed November 24, 2022. https://
Dermatol. 2020;140(7):1451-1455.e13. doi:10.1016/j.jid.2019.11.024 clinic altrials.gov/ct2/show/result s/NCT03619902
65. Akiyama M. Pustular psoriasis as an autoinflammatory kerati- 84. Todorović V, Su Z, Putman CB, et al. Small molecule IL-36γ antag-
nization disease (AiKD): genetic predisposing factors and prom- onist as a novel therapeutic approach for plaque psoriasis. Sci Rep.
ising therapeutic targets. J Dermatol Sci. 2022;105(1):11-17. 2019;9(1):9089. doi:10.1038/s41598-019-45626-w
doi:10.1016/j.jdermsci.2021.11.009 85. Mahil SK, Catapano M, Di Meglio P, et al. An analysis of IL-36 sig-
66. Kantaputra P, Chaowattanapanit S, Kiratikanon S, et al. SERPINA1, nature genes and individuals with IL1RL2 knockout mutations val-
generalized pustular psoriasis, and adult- onset immunodefi- idates IL-36 as a psoriasis therapeutic target [published correction
ciency. J Dermatol. 2021;48(10):1597-1601. doi:10.1111/134 appears in Sci Transl Med. 2017 Dec 13;9(420)]. Sci Transl Med.
6-8138.16081 2017;9(411):eaan2514. doi:10.1126/scitranslmed.aan2514
67. Ingelheim B. European Commission Approves SPEVIGO® (spe- 86. Sachen KL, Arnold Greving CN, Towne JE. Role of IL-36 cytokines
solimab) for Generalized Pustular Psoriasis Flares. Boehringer in psoriasis and other inflammatory skin conditions. Cytokine.
Ingelheim. Published December 13; 2022. Accessed December 2022;156:155897. doi:10.1016/j.cyto.2022.155897
28, 2022. https://www.boehringer-ingelheim.com/human-healt 87. Mercurio L, Failla CM, Capriotti L, et al. Interleukin (IL)-17/IL-36
h/skin-d iseas es/gpp/europ e an-c ommis sion-a pproves-s pevigo- axis participates to the crosstalk between endothelial cells and
spesolimab-generalized keratinocytes during inflammatory skin responses. PLoS One.
68. Berman HM, Westbrook J, Feng Z, et al. The protein data bank. 2020;15(4):e0222969. doi:10.1371/journal.pone.0222969
Nucleic Acids Res. 2000;28(1):235-242. doi:10.1093/nar/28.1.235 88. Chen WJ, Yu X, Yuan XR, et al. The role of IL-36 in the patho-
69. Liu S, Song X, Chrunyk BA, et al. Crystal structures of interleu- physiological processes of autoimmune diseases. Front
kin 17A and its complex with IL-17 receptor a. Nat Commun. Pharmacol. 2021;12:727956. Published 2021 Oct 5. doi:10.3389/
2013;4(1):1888. doi:10.1038/ncomms2880 fphar.2021.727956
70. Liu S, Griffor MC. Human Interleukin 17A. Published Online 2013. 89. Kim HS, You HS, Cho HH, et al. Two cases of generalized pustu-
71. Lupardus PJ, Garcia KC. The structure of interleukin-23 reveals the lar psoriasis: successful treatment with infliximab. Ann Dermatol.
molecular basis of p40 subunit sharing with interleukin-12. J Mol 2014;26(6):787-788. doi:10.5021/ad.2014.26.6.787
Biol. 2008;382(4):931-941. doi:10.1016/j.jmb.2008.07.051 90. Kara Polat A, Alpsoy E, Kalkan G, et al. Sociodemographic, clin-
72. Lupardus PJ, Garcia KC. Structure of Interleukin- 23. Published ical, laboratory, treatment and prognostic characteristics of 156
Online 2008. 10.2210/pdb3DUH/pdb generalized pustular psoriasis patients in Turkey: a multicentre
73. Eck MJ, Sprang SR. The structure of tumor necrosis factor-alpha case series. J Eur Acad Dermatol Venereol. 2022;36(8):1256-1265.
at 2.6 a resolution. Implications for receptor binding. J Biol Chem. doi:10.1111/jdv.18103
1989;264(29):17595-17605. doi:10.2210/pdb1tnf/pdb 91. Ko JM, Gottlieb AB, Kerbleski JF. Induction and exacerbation
74. Blair HA. Spesolimab: First approval. Drugs. 2022;83(17):1681- of psoriasis with TNF-blockade therapy: a review and anal-
1686. doi:10.1007/s40265-022-01801-4 ysis of 127 cases. J Dermatolog Treat. 2009;20(2):100-108.
75. Yuan ZC, Xu WD, Liu XY, Liu XY, Huang AF, Su LC. Biology of IL- doi:10.1080/09546630802441234
36 signaling and its role in systemic inflammatory diseases. Front 92. Xia P, Li YH, Liu Z, et al. Recalcitrant paradoxical pustular psori-
Immunol. 2019;10:2532. Published 2019 Oct 31. doi:10.3389/ asis induced by infliximab: two case reports. World J Clin Cases.
fimmu.2019.02532 2021;9(15):3655-3661. doi:10.12998/wjcc.v9.i15.3655
76. Byrne J, Baker K, Houston A, Brint E. IL-36 cytokines in inflam- 93. Yamasaki K, Nakagawa H, Kubo Y, Ootaki K, Japanese Brodalumab
matory and malignant diseases: not the new kid on the block any- Study Group. Efficacy and safety of brodalumab in patients with
more. Cell Mol Life Sci. 2021;78(17–18):6215-6227. doi:10.1007/ generalized pustular psoriasis and psoriatic erythroderma: results
s00018-021-03909-4 from a 52-week, open-label study. Br J Dermatol. 2017;176(3):741-
77. Murrieta-Coxca JM, Rodríguez-Martínez S, Cancino-Diaz ME, 751. doi:10.1111/bjd.14702
Markert UR, Favaro RR, Morales-Prieto DM. IL-36 cytokines: 94. Menter A, Strober BE, Kaplan DH, et al. Joint AAD-NPF guidelines
regulators of inflammatory responses and their emerging role of care for the management and treatment of psoriasis with bio-
in immunology of reproduction. Int J Mol Sci. 2019;20(7):1649. logics. J Am Acad Dermatol. 2019;80(4):1029-1072. doi:10.1016/j.
doi:10.3390/ijms20071649 jaad.2018.11.057
78. Campbell JJ, Ebsworth K, Ertl LS, et al. Efficacy of chemokine 95. Chiricozzi A, Romanelli M, Saraceno R, Torres T. No meaningful
receptor inhibition in treating IL-36α- induced Psoriasiform in- association between suicidal behavior and the use of IL-17A-
flammation. J Immunol. 2019;202(6):1687-1692. doi:10.4049/ neutralizing or IL-17RA-blocking agents. Expert Opin Drug Saf.
jimmunol.1801519 2016;15(12):1653-1659. doi:10.1080/14740338.2016.1228872
79. Iznardo H, Puig L. Exploring the role of IL-36 cytokines as a new 96. Yeroushalmi S, Chung M, Bartholomew E, Hakimi M, Koo J.
target in psoriatic disease. Int J Mol Sci. 2021;22(9):4344. Published Examining worldwide postmarketing suicides from biologics
2021 Apr 21. doi:10.3390/ijms22094344 used for psoriasis with a focus on brodalumab: a cross-sectional
|
1218 KODALI et al.
analysis using the Food and Drug Administration adverse event re- BMJ Open. 2014;4(11):e005602. Published 2014 Nov 12.
porting system (FAERS). JAAD Int. 2022;9:119-121. doi:10.1016/j. doi:10.1136/bmjopen-2014-0 05602
jdin.2022.08.010 113. Barbieri JS, Roe AH, Mostaghimi A. Simplifying contraception re-
97. Saeki H, Nakagawa H, Nakajo K, et al. Efficacy and safety of ixeki- quirements for iPLEDGE: a decision analysis. J Am Acad Dermatol.
zumab treatment for Japanese patients with moderate to severe 2020;83(1):104-108. doi:10.1016/j.jaad.2020.02.022
plaque psoriasis, erythrodermic psoriasis and generalized pustu- 114. Faulds D, Goa KL, Benfield P. Cyclosporin. A review of its phar-
lar psoriasis: results from a 52-week, open-label, phase 3 study macodynamic and pharmacokinetic properties, and therapeutic
(UNCOVER-J). J Dermatol. 2017;44(4):355-362. doi:10.1111/134 use in immunoregulatory disorders [published correction ap-
6-8138.13622 pears in drugs 1993 Sep;46(3):377] [published correction ap-
98. Imafuku S, Honma M, Okubo Y, et al. Efficacy and safety of secuk- pears in drugs. 1993 Sep;46(3):377]. Drugs. 1993;45(6):953-1040.
inumab in patients with generalized pustular psoriasis: a 52- doi:10.2165/00003495-199345060-0 0007
week analysis from phase III open-label multicenter Japanese 115. Kromer C, Loewe E, Schaarschmidt ML, et al. Drug survival in the
study. J Dermatol. 2016;43(9):1011-1017. doi:10.1111/134 treatment of generalized pustular psoriasis: a retrospective mul-
6-8138.13306 ticenter study. Dermatol Ther. 2021;34(2):e14814. doi:10.1111/
99. Suleiman AA, Khatri A, Oberoi RK, Othman AA. Exposure- dth.14814
response relationships for the efficacy and safety of Risankizumab 116. Robinson A, Van Voorhees AS, Hsu S, et al. Treatment of
in Japanese subjects with psoriasis. Clin Pharmacokinet. pustular psoriasis: from the medical Board of the National
2020;59(5):575-589. doi:10.1007/s40262-019-0 0829-2 Psoriasis Foundation. J Am Acad Dermatol. 2012;67(2):279-288.
100. Sano S, Kubo H, Morishima H, Goto R, Zheng R, Nakagawa H. doi:10.1016/j.jaad.2011.01.032
Guselkumab, a human interleukin-23 monoclonal antibody in 117. Del Campo M, Kosaki K, Bennett FC, Jones KL.
Japanese patients with generalized pustular psoriasis and erythro- Developmental delay in fetal aminopterin/methotrex-
dermic psoriasis: efficacy and safety analyses of a 52-week, phase ate syndrome. Teratology. 1999;60(1):10-12. doi:10.1002/
3, multicenter, open-label study. J Dermatol. 2018;45(5):529-539. (SICI)1096-9926(199907)60:1<10::AID-TERA5>3.0.CO;2-H
doi:10.1111/1346-8138.14294 118. Menter A, Cordoro KM, Davis DMR, et al. Joint American Academy
101. Ryan TJ, Baker H. Systemic corticosteroids and folic acid an- of Dermatology-National Psoriasis Foundation guidelines of care
tagonists in the treatment of generalized pustular psoriasis. for the management and treatment of psoriasis in pediatric pa-
Evaluation and prognosis based on the study of 104 cases. Br tients [published correction appears in J Am Acad Dermatol.
J Dermatol. 1969;81(2):134-145. doi:10.1111/j.1365-2133.1969. 2020 mar;82(3):574]. J Am Acad Dermatol. 2020;82(1):161-201.
tb15995.x doi:10.1016/j.jaad.2019.08.049
102. Hellgren L. Induction of generalized pustular psoriasis by topical 119. Bridgewood C, Cuthbert R, Wittmann M, McGonagle D. AB0054
use of betamethasone-dipropionate ointment in psoriasis. Ann Clin Pde4 inhibitor attenuation of il- 23 secretion from mononu-
Res. 1976;8(5):317-319. clear cells. Ann Rheum Dis. 2018;77(Suppl 2):1226. doi:10.1136/
103. Benjegerdes KE, Hyde K, Kivelevitch D, Mansouri B. Pustular annrheumdis-2018-eular.7287
psoriasis: pathophysiology and current treatment perspectives. 120. Li H, Zuo J, Tang W. Phosphodiesterase-4 inhibitors for the treat-
Psoriasis (Auckl). 2016;6:131-144. doi:10.2147/PTT.S98954 ment of inflammatory diseases. Front Pharmacol. 2018;9:1048.
104. Elias KM, Laurence A, Davidson TS, et al. Retinoic acid inhibits Th17 Published 2018 Oct 17. doi:10.3389/fphar.2018.01048
polarization and enhances FoxP3 expression through a Stat-3/ 121. Jeon C, Nakamura M, Sekhon S, et al. Generalized pustular pso-
Stat-5 independent signaling pathway. Blood. 2008;111(3):1013- riasis treated with apremilast in a patient with multiple medical
1020. doi:10.1182/blood-2007-06-096438 comorbidities. JAAD Case Rep. 2017;3(6):495-497. Published 2017
105. Umezawa Y, Ozawa A, Kawasima T, et al. Therapeutic guidelines Oct 6. doi:10.1016/j.jdcr.2017.07.007
for the treatment of generalized pustular psoriasis (GPP) based on 122. Georgakopoulos JR, Ighani A, Yeung J. Short-and long-term man-
a proposed classification of disease severity. Arch Dermatol Res. agement of an acute pustular psoriasis flare: a case report. J Cutan
2003;295(1):S43-S54. doi:10.1007/s00403-0 02-0371-6 Med Surg. 2017;21(5):452-456. doi:10.1177/1203475417712499
106. Zhu T, Jin H, Shu D, Li F, Wu C. Association of IL36RN muta- 123. GHO | By category | Median availability of selected generic med-
tions with clinical features, therapeutic response to acitretin, icines - Data by country. WHO. Accessed December 23, 2022.
and frequency of recurrence in patients with generalized pustu- https://apps.who.int/gho/data/node.main.488?lang=en
lar psoriasis. Eur J Dermatol. 2018;28(2):217-224. doi:10.1684/ 124. Samotij D, Szczęch J, Reich A. Generalized pustular psori-
ejd.2018.3245 asis: divergence of innate and adaptive immunity. Int J Mol
107. Draghici CC, Miulescu RG, Petca RC, Petca A, Dumitrașcu M, Sci. 2021;22(16):9048. Published 2021 Aug 22. doi:10.3390/
Șandru F. Teratogenic effect of isotretinoin in both fertile females ijms22169048
and males (review). Exp Ther Med. 2021;21(5):534. doi:10.3892/ 125. Lu J, Shi Y. A review of disease burden and clinical management for
etm.2021.9966 generalized pustular psoriasis in China. Expert Rev Clin Immunol.
108. Larsen FG, Jakobsen P, Knudsen J, Weismann K, Kragballe 2022;18(10):1023-1032. doi:10.1080/1744666X.2022.2118716
K, Nielsen-Kudsk F. Conversion of acitretin to etretinate in 126. Komine M, Morita A. Generalized pustular psoriasis: current
psoriatic patients is influenced by ethanol. J Invest Dermatol. management status and unmet medical needs in Japan. Expert
1993;100(5):623-627. doi:10.1111/1523-1747.ep12472293 Rev Clin Immunol. 2021;17(9):1015-1027. doi:10.1080/17446
109. Vos LE, Vermeer MH, Pavel S. Acitretin induces capillary leak syn- 66X.2021.1961580
drome in a patient with pustular psoriasis. J Am Acad Dermatol.
2007;56(2):339-3 42. doi:10.1016/j.jaad.2006.08.006
110. Estival JL, Dupin M, Kanitakis J, Combemale P. Capillary leak syn-
drome induced by acitretin. Br J Dermatol. 2004;150(1):150-152.
How to cite this article: Kodali N, Blanchard I, Kunamneni S,
doi:10.1111/j.1365-2133.2004.05771.x
111. Cuhadaroglu C, Korular D, Erelel M, Kiyan E, Kiliçaslan Z. Lebwohl MG. Current management of generalized pustular
Respiratory distress with acitretin, reversal by corticosteroid. psoriasis. Exp Dermatol. 2023;32:1204-1218. doi:10.1111/
Dermatol Online J. 2001;7(2):5. exd.14765
112. Zomerdijk IM, Ruiter R, Houweling LM, et al. Isotretinoin exposure
during pregnancy: a population-based study in The Netherlands.

Experimental Dermatology - 2023 - Kodali - Current Management of Generalized Pustular Psoriasis

Uploaded by

Copyright:

Available Formats

Experimental Dermatology - 2023 - Kodali - Current Management of Generalized Pustular Psoriasis

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Experimental Dermatology - 2023 - Kodali - Current Management of Generalized Pustular Psoriasis

Uploaded by

Copyright:

Available Formats

Received: 28 November 2022 | Revised: 6 January 2023 | Accepted: 8 February 2023

Current management of generalized pustular psoriasis

Nilesh Kodali1 | Isabella Blanchard1 | Sruthi Kunamneni1 | Mark G. Lebwohl2

1 | I NTRO D U C TI O N subtype of psoriasis, is associated with innate immune system over-

Deficiency in the MPO gene encoding myeloperoxidase has only

Folic acid antagonists such as methotrexate may also be used to

7. Kharawala S, Golembesky AK, Bohn RL, Esser D. The clinical, hu-

You might also like